The long-range aim of the proposed research is to understand the role central nervous system neurotransmitter systems play in the mediation of the actions of psychotropic drugs and in the maintenance of behavior. Experimental work over the past several years has suggested that, as neurotransmitters in the central nervous system are modified by drugs, behavior is modified, and further, that both behavior and the environment also have an effect on neurotransmitter function. Hence, an interactive state exists between the brain, neurotransmitters and drugs on the one hand and the environment, behavior and neurotransmitters on the other. It is within this conceptual framework that we will pursue specific research projects in the coming years. We will focus on dopamine, norepinephrine, 5-hydroxytryptamine and gamma amino butyric acid, and their relationship to operant behavior, feeding, drinking and locomotion. The actions of neurotransmitters will be modified by drugs and/or neurotoxin. Behavior will be measured using computer-oriented techniques. We will attempt to identify changes in neurotransmitter systems that occur when operant behavior is modified by administration of antidepressant drugs. The goal of this research is to elucidate changes in central nervous system neurochemistry which lead to changes in behavior and which may be involved in the pathophysiology of depression, and attempt to identify neurochemical mechanisms in the central nervous system that account for drug-behavior- environment interactions to further understand the relative roles of drugs and the environment in modifications of behavior. The second aim of the research proposed is to determine whether the long-term alterations in monoamine levels and morphological signs of degeneration -- that we have demonstrated previously in our research on the neurotoxicity produced by administration of amphetamines -- is also produced by other commonly prescribed or abused anorectic and psychomotor stimulant drugs. We will study long-term behavioral changes associated with monoaminergic toxicity produced by methamphetamine and hallucinogenic amphetamine analogues, including MDA and MDMA ((plus/minus)-3,4-methylenedioxymethamphetamine and cocaine. We will continue to examine in detail the mechanism by which methamphetamine and related drugs produce neurotoxic effects. Our results to date have indicated that 6-hydroxydopamine and 5,6-dihydroxytryptamine are formed in brain after a large dose of methylamphetamine. The relationship between the oxidative stress hypothesis and the fact that the blockade of the n-methyl-d-aspartate receptor in protecting against neurotoxicity will also be investigated.